MI-3454 (MI 3454) is a highly potent, orally bioavailable inhibitor of the menin-MLL1 interaction with IC50 of 0.51 nM, 60-fold improvement over MI-503.
MI-3454 inhibits growth of human MLL leukemic cell lines (MLL-tr): MV-4-11, MOLM-13, KOPN-8, SEM, RS4-11 with GI50 values of 7-27 nM in MTT cell viability assays, does not significantly (>100-fold) affect the growth of leukemic cells without MLL1 translocations.
MI-3454 (50 nM or lower) led to downregulated expression of HOXA9 and MEIS1 in MV-4-11 and MOLM13 cells, also reduced other MLL fusion target genes, including MEF2C, DLX2, HOXA10, PBX3, and FLT3.
MI-3454 demonstrated strong reduction of cell proliferation and downregulation of HOXA9 and MEIS1 expression in mouse bone marrow cells transformed with the MLL-AF9 oncogene but not in bone marrow cells transformed with HOXA9 and MEIS1 oncogenes.
MI-3454 induces leukemia regression in xenograft model of MLL leukemia through on-target activity.
MI-3454 (3–12 nM) substantially reduced clonogenic potential in MLL leukemia patient samples with MLL1 translocations or NPM1 mutations, MI-3454 induced complete remission or blocks leukemia progression in PDX models of MLL leukemia.